Type 2 diabetes (T2D) has reached epidemic proportions in the United States, affecting an estimated 8.3% of the population and inflicting enormous personal, public health, and financial tolls. Unfortunately, the cellular and molecular abnormalities that confer genetic and environmentally- determined diabetes risk remain incompletely understood. Thus, finding genes and pathways linked to T2D risk is essential for developing new and improved approaches to prevention and treatment. Recent studies from the Patti Lab have identified a novel, unexpected pattern of gene expression in skeletal muscle from human patients with established T2D. This pattern includes increased expression of genes regulated by serum response factor (SRF) and its upstream regulatory protein STARS (striated muscle activator of Rho-dependent signaling). Moreover, STARS expression correlates inversely with insulin resistance. Importantly, this pattern is also present in those at risk for disease based on family history, potentially linking this to risk for T2D (Jin and Patti, JCI 2011) Preliminary data indicate that the STARS-SRF pathway can robustly regulate muscle insulin resistance and systemic metabolism, contributing to T2D pathophysiology. Specifically, activation of STARS-SRF induces insulin resistance and reduces fatty acid oxidation, while inhibition of SRF or reduced STARS expression improves mitochondrial oxidative metabolism and increases insulin- stimulated glucose transport in myotubes. Moreover, STARS-null mice are resistant to diet-induced obesity and glucose intolerance, potentially via increased exercise capacity and energy expenditure. This proposal focuses on testing the innovative hypothesis that activation of STARS-SRF plays a pivotal role in promoting insulin resistance, and that inhibition of this pathway is a novel therapeutic approach for T2D. Three specific aims are proposed to test these hypotheses and to elucidate molecular mechanisms mediating these effects: (1) To determine the metabolic consequences of STARS-SRF activation, by assessing insulin action, glucose transport, and oxidative metabolism in myotubes overexpressing STARS and in muscle-specific STARS transgenic mice. (2) To identify mechanisms by which STARS-SRF modulates oxidative metabolism and insulin sensitivity by detailed analysis of mitochondrial mass/function & insulin signaling in primary myotubes from both STARS-null and STARS-transgenic mice. Since preliminary data indicate that STARS-SRF inhibition activates AMP kinase, we will test whether STARS effects on oxidative metabolism are mediated via AMP kinase. (3) To utilize specific SRF inhibitors to dissect pathways mediating improved insulin action and oxidative metabolism in cultured myotubes, and determine whether these inhibitors can similarly improve glucose metabolism and energy expenditure in vivo, in mice with obesity and T2D.